Blood Coagulation Cascade

International Number or Term	Plasma Factor and Alternative Names	Cause or Description of Deficiency
I	Fibrinogen	Liver Disease
II	Prothrombin	Liver Disease or Vitamin K Deficiency
III	TF, Thromboplastin	Deficiency of TF probably does not occur
IV	Ca++	Never Deficient without Tetany
V	Proaccelerin	Parahemophilia, Rare
VII	Proconvertin	Liver Disease or Vitamin K Deficiency
VIII	Antihemophilic Globulin, AHF A	Hemophilia A, 80% of Hemophilics
IX	Christmas Factor, AHF B	Hemophilia B (Christmas Disease), Depressed with Vitamin K Deficiency
X	Stuart-Prower Factor	Liver Disease or Vitamin K Deficiency
XI	Plasma Thromboplastin Antecedent, AHF C	Factor XI Hemophilia (Hemophilia C)
XII	Hageman Factor	Generally No Clinical Symptoms but may have Thromboses, Rare
XIII	Fibrin-Stabilizing Factor, Laki-Lorand Factor, Fibrinase	Delayed Bleeding, Defective Healing, Rare
PF3	Platlet Factor 3	Thrombocytopenia
-	Protein C	Liver Disease or Vitamin K Deficiency
-	Protein S	Liver Disease or Vitamin K Deficiency
-	Protein M	Liver Disease or Vitamin K Deficiency
vWF	von Willebrand Factor	vWD Types I, IIa, IIb, IIc, III
Pre-K	Prekallikrein, Fletcher Factor
HMWK	High-Molecular-Weight Kininogen

Extrinsic Pathway

The main role of the extrinsic pathway is to create a "thrombin burst," a process by which thrombin is released instantaneously. Factor VIIa circulates in a higher amount than any other activated coagulation factor.

• Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF) expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
• TF-FVIIa activates FIX and FX.
• FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa.
• The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).
• FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.
• Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates FXI, which, in turn, activates FIX), and activates and releases FVIII from being bound to vWF.
• FVIIIa is the co-factor of FIXa, and together they form the "tenase" complex, which activates FX; and so the cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)

Intrinsic Pathway

The intrinsic pathway begins with formation of the primary complex on collagen by high-molecular-weight kiniogen (HMWK), prekallikrein, and Factor XII (Hageman Factor). Prekallikrein is converted to kallikrein and Factor XII becomes Factor XIIa. Factor XIIa converts Factor XI into Factor XIa. Factor XIa activates Factor IX, which with its co-factor Factor VIIIa form the tenase complex, which activates Factor X to Xa. The minor role that the intrinsic pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of Factor XII, HMWK, and prekallikrein do not have a bleeding disorder. Instead, intrinsic pathway seems to be more involved in inflammation. Patients without Factor XII (Hageman Factor) suffer from constant infection.

Common Pathway

Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, it activates Factors VIII and Factor V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fribrin polymers that form from activated monomers. Factor XIII converts to Factor XIIIa. Factor XIIIa is necessary because fibrin is stabilized by factor XIIIa.
Following activation by the contact factor of tissue factor pathways, the coagulaton cascade is maintained in a prothrombotic state by the continued activation of Factor VIII and Factor IX to form the tenase complex, until it is down-regulated by the anticoagulant pathways

Cofactors

• Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles or microvesicles shed from them. Calcium is also required at other points in the coagulation cascade.

• Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z. In adding the gamma-carboxyl group to glutamate residues on the immature clotting factors Vitamin K is itself oxidized. Another enzyme, Vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important as a target for anticoagulant drugs warfarin and related coumarins such as acenocoumarol, phenprocoumon, and dicumarol. These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors. Other deficiencies of vitamin K (e.g., in malabsorption), or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence); this causes partial or non-gamma carboxylation, and affects the coagulation factors' ability to bind to expressed phospholipid.

Regulators

• Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC). Protein C is activated in a sequence that starts with Protein C and thrombin binding to a cell surface protein thrombomodulin. Thrombomodulin binds these proteins in such a way that it activates Protein C. The activated form, along with protein S and a phospholipid as cofactors, degrades FVa and FVIIIa. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant of Factor V or high levels of FVIII also may lead to a thrombotic tendency.

• Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases: thrombin, FIXa, FXa, FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan sulfate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria) leads to thrombophilia.

• Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FIX and FX.

• Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.

• Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn, activates adenylyl cyclase, which synthesizes cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade.